Michael Zech1,2, Daniel D Lam1, Juliane Winkelmann3,4,5,6. 1. Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Munich, Neuherberg, Germany. 2. Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 3. Institut für Neurogenomik, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764, Munich, Neuherberg, Germany. juliane.winkelmann@tum.de. 4. Institut für Humangenetik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. juliane.winkelmann@tum.de. 5. Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany. juliane.winkelmann@tum.de. 6. Munich Cluster for Systems Neurology, SyNergy, Munich, Germany. juliane.winkelmann@tum.de.
Abstract
PURPOSE OF REVIEW: To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome. RECENT FINDINGS: Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2B haploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients. DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor.
PURPOSE OF REVIEW: To summarize the molecular and clinical findings of KMT2B-related dystonia (DYT-KMT2B), a newly identified genetic dystonia syndrome. RECENT FINDINGS: Since first described in 2016, 66 different KMT2B-affecting variants, encompassing a set of frameshift, nonsense, splice-site, missense, and deletion mutations, have been reported in 76 patients. Most mutations are de novo and expected to mediate epigenetic dysregulation by inducing KMT2Bhaploinsufficiency. DYT-KMT2B is characterized phenotypically by limb-onset childhood dystonia that tends to spread progressively, resulting in generalized dystonia with cranio-cervical involvement. Co-occuring signs such as intellectual disability are frequently observed. Sustained response to deep brain stimulation (DBS), including restoration of independent ambulation, is seen in 93% (27/29) of patients. DYT-KMT2B is emerging as a prevalent monogenic dystonia. Childhood-onset dystonia presentations should prompt a search for KMT2B mutations, preferentially via next-generation-sequencing and genomic-array technologies, to enable specific counseling and treatment. Prospective multicenter studies are desirable to establish KMT2B mutational status as a DBS outcome predictor.
Entities:
Keywords:
Childhood dystonia; De novo mutation; Deep brain stimulation; Generalized dystonia; Haploinsufficiency; Lysine-specifc methyltransferase family
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